Inflammatory Th17 Cells Express Integrin α v β 3 for Pathogenic Function

Abstract

SUMMARY Inerleukin-23 (IL-23) is required for inflammatory Th17 cell function in experimental autoimmune encephalomyelitis (EAE), and IL-23 blockade reduces the number of effector Th17 cells in the CNS. We report that pro-inflammatory Th17 cells express high integrin β3 that is IL-23 dependent. Integrin β3 was not upregulated on all activated T cells; rather, integrin β3 was upregulated along with its functional partner integrin αv on effector Th17 cells and “ex-Th17” cells, and αvβ3hi RORγt+ cells expanded during EAE. Integrin αvβ3 inhibitors ameliorated clinical signs of EAE, and integrin β3 deficiency on CD4+ T cells alone was sufficient to block EAE induction. Furthermore, integrin-β3-deficient Th17 cells, but not Th1 cells, were impaired in their ability to induce EAE. Integrin β3−/− T cells induced smaller demyelinated lesions and showed reduced spread and accumulation within the CNS, corresponding with impaired extracellular-matrix-mediated migration. Hence, integrin β3 is required for Th17 cell-mediated autoimmune CNS inflammation.

Noncanonical STAT3 activity sustains pathogenic Th17 proliferation and cytokine response to antigen

“…IL-23R blockade results in reduced production of IL-17 and IFN-γ by day 10 after immunization for EAE, whether measured by PMA and ionomycin stimulation or antigen stimulation with MOG(35-55) (McGeachy et al, 2009). In contrast, STAT3 deletion after IL-17 production did not affect PMA-and ionomycin-elicited cytokine production or expression of other previously identified IL-23-dependent effector molecules (Codarri et al, 2011;Du et al, 2016;El-Behi et al, 2011;Hirota et al, 2011;Jain et al, 2016;McGeachy et al, 2009). This disparity could perhaps be explained by the fact that the absolute requirement for IL-23 signaling in Th17 cell effector function (at least in the EAE model) occurs within the first 5 d in vivo, despite the functional outcomes of IL-23 blockade in the presence or absence of the STAT3 inhibitor cryptotanshinone for 19 h; IL-17A was assessed in the supernatant by ELISA (D), and TMRE was assessed by flow cytometry (E).…”

“…We therefore further investigated whether STAT3 deletion mimicked IL-23R blockade. Surprisingly, expression of factors previously identified to be regulated by IL-23 in effector Th17 cells was in fact unchanged following STAT3 deletion (Codarri et al, 2011;Du et al, 2016;El-Behi et al, 2011;Hirota et al, 2011;Jain et al, 2016;McGeachy et al, 2009). These included receptors for IL-23, IL-1β, and IL-7; the migration mediator integrin β3; and the transcription factor Blimp1 (encoded by Prdm1; Fig.…”

Sialomucin CD43 regulates T helper type 17 cell intercellular adhesion molecule 1 dependent adhesion, apical migration and transendothelial migration

“…However, blocking LFA‐1, the main ligand of ICAM‐1 in T cells, has not proved to be effective in preventing disease . Recently, Th17 cells have been reported to use integrin β 3 to migrate to the CNS during EAE; hence, the protection observed in CD43 −/− mice could also be attributed to impaired interactions of CD43 −/− Th17 cells with integrin β 3 ligands such as fibronectin. However, our in vitro data indicate that WT and CD43 −/− Th17 cells adhered to fibronectin in similar numbers, suggesting that the protection of CD43 −/− mice from EAE may be independent of integrin β 3 ‐mediated Th17 cell recruitment, although this would require in vivo confirmation.…”

“…5,30,55 However, blocking LFA-1, the main ligand of ICAM-1 in T cells, has not proved to be effective in preventing disease. 56 Recently, Th17 cells have been reported to use integrin b 3 to migrate to the CNS during EAE; 42 hence, the protection observed in CD43 À/À mice could also be attributed to impaired interactions of CD43 À/À Th17 cells with integrin b 3 ligands such as fibronectin.…”

Pivotal role for α V integrins in sustained Tfh support of the germinal center response for long-lived plasma cell generation

“…Targeting α V integrins may enable novel therapeutic control of Tfh GC numbers to boost immunity or mitigate Ab-mediated autoimmune pathology. (32,33), TGF-β activation (34)(35)(36), Toll-like receptor signal strength (37)(38)(39), and cell migration (40,41).…”